Tolerance & Tachyphylaxis

Tolerance

Decreased pharmacological response of drug on repeated exposure, requiring larger subsequent doses for the same effect.

Tachyphylaxis

When tolerance occurs rapidly, in a dose-independent manner

Mechanisms

• Tolerance
  • Pharmacodynamic tolerance
    Persistent, high concentrations of ligand, causes receptor downregulation (decreased expression, affinity or activity)
    • e.g. Opioid tolerance → continual exposure leads to receptor de-coupling with the G-Protein, or decreased endocytosis-cycling leading to decreased second messenger pathway on ligand binding
  • Pharmacokinetic tolerance
    Persistent exposure to drug may induce expression of clearance mechanisms (induction of CYP450 enzymes in liver) leading to decreased drug reaching effect site
    • e.g. Ethanol tolerance → Induction of alcohol dehydrogenase reduce bioavailability of alcohol due to increased first pass metabolism
  • Behavioral tolerance
    Diminution of a drug-induced disruption of a goal-oriented behavior that is dependent on a learning process
    • e.g. Psychoactive drugs

• Tachyphylaxis
  • Depletion of intracellular stores of an effector, before resynthesis may occur
    • e.g. Ephedrine tachyphylaxis occurs due to depletion of stored noradrenaline

Sakurai 2016

Answer by Sakurai